Although diabetic nephropathy occurs in only a minority of patients with diabetes, it is the major cause of end-stage renal disease in the United States. Hyperglycemia and hypertension are important factors predisposing patients to diabetic nephropathy, but accumulating evidence points to critical genetic factors predisposing only a subset of patients with diabetes to nephropathy. It has been challenging to define the genes conferring risk for nephropathy in human populations. Comparative genomics using the robust genetic reagents available in laboratory mice should provide a complementary approach to defining genes that may predispose to diabetic nephropathy in mice and humans. This article reviews new studies to identify genetic risk factors for diabetic nephropathy and the unique approaches that may be used to elucidate the genetic pathogenesis of this disorder in mice.